Bottom Line:
Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs.Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype.Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo.

ABSTRACTBeside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR(1) and 5-HTR(2) receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR(3), 5-HTR(4) and 5-HTR(7) receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders.

pone-0006453-g006: 5-HT modulates T-cell priming capacity of human monocyte-derived DCs.Immature DCs were left untreated or stimulated with 5-HT, or were induced to undergo maturation with LPS in the absence or the presence of indicated concentration of 5-HT for 24 h. DCs were then used to prime purified allogeneic CD4+CD45RA+ naive T cells. After 5 days, supernatants from T cells were evaluated for the secretion of IL-5 (A), IL-13 (B) and IFN-γ (C). Results are expressed as mean pg/ml±SD (n = 3). *p<0.05 between cytokines secreted by T cells stimulated with DC treated or not with 5-HT. (D) Naive mice received 10×106 DO11.10 CD4+ T-cells intravenously on day-2. On day 0 mice were instilled intratracheally with 106 OVA-pulsed, OVA-pulsed 5-HT treated DCs, or unpulsed DCs. On day4 mediastinal lymph node cells were collected and cultured for 4 days. Four days later, supernatants were harvested and analyzed for the presence of IL-4, IL-5, IL-13, and IFN-γ using commercially available ELISAs .

Mentions:
Starting from our observation that activation of 5-HTR4 and 5-HTR7 subtypes inhibited the production of IL-12p70, which is an important factor influencing the differentiation of Th1 cells, we next analyzed the quality of primary T cell response induced by DC matured in the presence of different concentration of 5-HT. Naive CD4+CD45RA+ allogeneic T cells primed with mDC exposed to various concentration of 5-HT during maturation displayed an impaired Th1 and enhanced Th2 polarization, as determined by the increased production of IL-13 and IL-5 as well as down regulation of IFN-γ (Fig. 6). T cells stimulated with 5-HT pre-treated iDC showed an also higher IL-5 and IL-13 secretion (Fig. 6A/B).

pone-0006453-g006: 5-HT modulates T-cell priming capacity of human monocyte-derived DCs.Immature DCs were left untreated or stimulated with 5-HT, or were induced to undergo maturation with LPS in the absence or the presence of indicated concentration of 5-HT for 24 h. DCs were then used to prime purified allogeneic CD4+CD45RA+ naive T cells. After 5 days, supernatants from T cells were evaluated for the secretion of IL-5 (A), IL-13 (B) and IFN-γ (C). Results are expressed as mean pg/ml±SD (n = 3). *p<0.05 between cytokines secreted by T cells stimulated with DC treated or not with 5-HT. (D) Naive mice received 10×106 DO11.10 CD4+ T-cells intravenously on day-2. On day 0 mice were instilled intratracheally with 106 OVA-pulsed, OVA-pulsed 5-HT treated DCs, or unpulsed DCs. On day4 mediastinal lymph node cells were collected and cultured for 4 days. Four days later, supernatants were harvested and analyzed for the presence of IL-4, IL-5, IL-13, and IFN-γ using commercially available ELISAs .

Mentions:
Starting from our observation that activation of 5-HTR4 and 5-HTR7 subtypes inhibited the production of IL-12p70, which is an important factor influencing the differentiation of Th1 cells, we next analyzed the quality of primary T cell response induced by DC matured in the presence of different concentration of 5-HT. Naive CD4+CD45RA+ allogeneic T cells primed with mDC exposed to various concentration of 5-HT during maturation displayed an impaired Th1 and enhanced Th2 polarization, as determined by the increased production of IL-13 and IL-5 as well as down regulation of IFN-γ (Fig. 6). T cells stimulated with 5-HT pre-treated iDC showed an also higher IL-5 and IL-13 secretion (Fig. 6A/B).

Bottom Line:
Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs.Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype.Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo.

ABSTRACTBeside its well described role in the central and peripheral nervous system 5-hydroxytryptamine (5-HT), commonly known as serotonin, is also a potent immuno-modulator. Serotoninergic receptors (5-HTR) are expressed by a broad range of inflammatory cell types, including dendritic cells (DCs). In this study, we aimed to further characterize the immuno-biological properties of serotoninergic receptors on human monocyte-derived DCs. 5-HT was able to induce oriented migration in immature but not in LPS-matured DCs via activation of 5-HTR(1) and 5-HTR(2) receptor subtypes. Accordingly, 5-HT also increased migration of pulmonary DCs to draining lymph nodes in vivo. By binding to 5-HTR(3), 5-HTR(4) and 5-HTR(7) receptors, 5-HT up-regulated production of the pro-inflammatory cytokine IL-6. Additionally, 5-HT influenced chemokine release by human monocyte-derived DCs: production of the potent Th1 chemoattractant IP-10/CXCL10 was inhibited in mature DCs, whereas CCL22/MDC secretion was up-regulated in both immature and mature DCs. Furthermore, DCs matured in the presence of 5-HT switched to a high IL-10 and low IL-12p70 secreting phenotype. Consistently, 5-HT favoured the outcome of a Th2 immune response both in vitro and in vivo. In summary, our study shows that 5-HT is a potent regulator of human dendritic cell function, and that targeting serotoninergic receptors might be a promising approach for the treatment of inflammatory disorders.